Method and composition for preventing, reducing and reversing ocular ischemic neuronal damage

ABSTRACT

Methods and compositions are provided for preventing, reducing and reversing ischemic neuronal damage related to congenital and acquired ophthalmologic conditions such as macular degeneration, retinitis pigmentosa, optic neuritis, neuroretinitis, Lebers congenital amaurosis, Stargardts disease, Parkinson&#39;s disease, diabetic retinopathy, idiopathic senile vision loss, uveitis, edema and ocular surgery. An amount of an acetylcholine esterase inhibitor containing composition is administered to the eye of a mammal, either topically or via a controlled-release drug delivery system.

This application claims the benefit of U.S. Provisional Application No.60/465,476 filed Apr. 25, 2003, which application is hereby incorporatedby reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to a method and composition for treatingand preventing ocular neuronal damage with periodic administrations ofan acetylcholinesterase inhibitor. Specifically, the invention providesmethod and composition for treatment and prevention of congenital andacquired conditions (ischemic or non-ischemic) which threaten the nervesof the visual system of mammals; these conditions include but are notlimited to: macular degeneration, retinitis pigmentosa, optic neuritis,neuroretinitis, Lebers congenital amaurosis, Stargardt disease,Parkinson's disease related vision loss, diabetic retinopathy,idiopathic senile vision loss, uveitis, edema and ocular surgery.

BACKGROUND OF THE INVENTION

The health of a mammalian visual system is dependent upon the propervascular perfusion of all constituent eye components, including: theretina, macula, choroid, sclera, ciliary body, conjunctiva and opticnerve. Afferent and efferent blood flow is critical to supplyingnutrients, maintaining osmotic balances and removing waste products. Themammalian eye is vulnerable to many congenital and acquired focalischemic conditions which can deprive the visual system of proper bloodsupply. Focal ischemia occurs under conditions in which a portion of thevisual system is deprived of its normal blood supply, such as may resultfrom choroidal neovascularization, the formation of drusen, reductionsin ciliary activity, uveitis, edema, ocular surgery, traumatic injury,inherited diseases or visual pathway tumors. Focal ischemic conditionshave the potential for producing widespread neuronal damage, even if theischemic condition is transient. Much of this neuronal damage isattributed to secondary consequences of reperfusion of the tissue, suchas the release of vasoactive products by damaged endothelium, and therelease of cytotoxic products (free radicals, leukotrienes, etc.) bydamaged tissues.

For decades, it has been demonstrated that within the mammalian visualnervous system, a phenomenon known as neuronal cell death takes place.This cell death is regulated by the release of neurotrophins.Neurotrophins are a family of small polypeptides, which bind to lowaffinity receptors throughout the visual system. Pereira, S. P. F.,Araujo, E. G., 2000. Chronic Depolarization induced by veratridineincreases the survival of rat retinal ganglion cells after 48 hours ‘invitro’. Int. J. Dev. Neurosci. 18, 773-780.

Acetylcholine (ACh), the first neurotransmitter to be identified (Daleet al., 1936, Release of acetylcholine at voluntary motor nerve endings.J. Physiol. Lond. 82, 121-128) has recently been shown that anenhancement in ACh activity reduces neural cell death (Rinner, J.,Kukulanky, T., Flesner, P., Skreiner, E., Globerson, A., Kasai, M.,Hirokawa, K., Korsako, W., Schauenstein, K., 1994. Cholinergicstimulation modulates apoptosis and differentiation of murine thymocytesvia A nicotinic effect on thymic epthelium. Biochem. Biophys. Res. Corn.203, 1057-1062) and the death of related Purkinje cells (Mount et al.,1994, J. Neurochem. 63, 2065-2073).

The role of cholinergic activity in the differentiation and survival ofretinal neurons is not well understood. It has been previouslydemonstrated that treatment with veratridine increases the survival ofretinal ganglion cells. This effect was blocked by atropine indicatingthe importance of cholinergic activity on neuronal survival (Pereira etal., 2000, Int. J. Dev. Neurosci. 18, 773-780). Within the innerplexiform layer of the retina, muscarinic receptors have been identifiedon processes from all three inner retinal neuron types; in the outerplexiform layer, muscarinic receptors are critical to the functioning ofsecond-order cells, with highest densities along the bipolar dendrites(Calaza et al., 2000, Brazirian J. Med & Biol Res. 33: 1075-1082).Niemeyer, et al., (1995) explored the impact of applying a muscarinicantagonist (Quinuclidinyl benzilate) to block of retinal cholinergicreception. They observed a dose-related decrease in retinal perfusion,suggesting a substantial contribution of muscarinic cholinergictransmission toward retinal viability (Niemeyer et al., 1995, KlinMonatsbl Augenheilkd., 206 (5): 380-383).

The healthy activity level of afferent cells such as rods and coneswithin the retina also plays an important role in regulating neuronalcell death. The blockade of electrical activity of afferent cells suchas these will, in itself, induce neuronal degeneration within targetcells. As cellular wastes build up between the RPE and Bruch's membrane,metabolic efficiency is disrupted and the overlying photoreceptorsbecome ischemic and nonfunctional (Hageman et al., 2001, Prog Retin EyeRes., 20(6): 705-32).

These reports directly or indirectly focus on arriving at solutions tothe regulation of neuronal activities and to the alleviation of visualdisabilities. There is, however, a need for a simple and an effectivemethod and composition for treatment and prevention of congenital andacquired ischemic conditions such as macular degeneration, retinitispigmentosa, optic neuritis, neuroretinitis, Lebers congenital amaurosis,Stargardt disease, Parkinson's-related vision loss, diabeticretinopathy, solar retinopathy, retinal detachment, idiopathic senilevision loss, uveitis and edema. These conditions often threaten thenerves of the visual system of mammals.

In this regard, the U.S. Pat. No. 6,313,155 is of relevance because itdiscloses certain compositions and methods for increasing retinal bloodflow and particularly for treating visual disabilities, such as maculardiseases. In particular, it discloses that a topical carbonic anhydraseinhibitor in combination with an ocular hypotensive agent or inotropicagent either to the eye or systemically is effective to increasevascular perfusion and to treat macular edema and macular degeneration.It also reports that eye pressure reducing drugs or agents, whenadministered alone without a carbonic anhydrase inhibitor, tend toproduce minimal changes in circulation and vision, and may in certaininstances actually diminish both.

SUMMARY OF THE INVENTION

In the present invention it is discovered, quite unexpectedly, thattopical administration of acetylcholine esterase inhibitor to one orboth eyes of the mammal affected by or vulnerable to ocular neuronaldamage provides a profound beneficial effect (e.g., significantimprovement in visual acuity) without any need for other inhibitors suchas, for example, a topical carbonic anhydrase inhibitor. According tothe present inventor's experience, the inclusion of carbonic anhydraseinhibitor into the topical composition was found to be unnecessary andassociated with undesirable effects in achieving the goals of thepresent invention. It is believed that the acetylcholine esteraseinhibitor causes increased ciliary activity, trabecular flow andchoroidal perfusion within the mammalian eye and thereby significantlyimproving or at least stabilizing visual acuity.

Accordingly, the present invention provides a method and composition forpreventing, reducing and reversing ocular neuronal damage related tovarious conditions (ischemic or non-ischemic conditions) affecting thevisual system of a mammal. The composition has or consists essentiallyof an amount of an acetylcholine esterase inhibitor The presentinvention particularly provides a method of reducing neuronal damagerelated to an ischemic condition.

Specifically, the invention provides methods for preventing, reducing orreversing ocular neuronal damage and/or methods for improving visualacuity by topical administration of acetylcholine esterase inhibitor(s)to patients diagnosed with the following condition(s) and in need suchtherapeutic/prophylactic methods: macular degeneration, retinitispigmentosa, optic neuritis, optic neuropathy, generalized optic nerveischemia, neuroretinitis, Lebers congenital amaurosis, Stargardtdisease, Parkinson's disease, diabetic retinopathy, idiopathic senilevision loss, uveitis, edema, ocular surgery, a thromboembolic event inthe retinal vasculature, a visual scotoma, a retinal migraine,ophthalmoplegic migraine or scintillating scotoma, central retinalartery/vein occlusion, branch retinal artery/vein occlusion, anteriorischemic optic neuropathy, giant cell arteritis, retinal hemorrhage,cystoid macular edema, macular cystic degeneration, preretinal fibrosis,ischemic maculopathy, macular holes and cysts, macular epithelialfibrosis, peripapillary staphyloma and peripapillary atrophy, acutemacular neuroretinopathy and/or Plaquenil-related toxicity.

In the present invention, it has been found that(2-mercaptoethyl)trimethylammonium iodide O,O-diethyl phosphorothioatesold as PHOSPOHLINE IODIDE® (also known as echothiophate) within itstraditional dosage regimens reported in the prior art, does not exhibitthe desired therapeutic effects described herein but it surprisingly iseffective at very low concentrations, for example, of about 0.02% to0.15% or even lower 0.01% to exhibit the desired therapeutic effects

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method and composition for treatingand preventing ischemic ocular neuronal damage and for improving visualacuity with periodic administrations of an acetylcholinesteraseinhibitor. In particular, this invention utilizes the application of anophthalmic acetylcholinesterase inhibitor, or pharmaceutical equivalentthereof, at low doses, to increase ocular Ach (acetyl choline)availability and thereby heighten muscarinic activity, ganglionic signaland retinal perfusion.

It is believed by the present inventor that the present treatmentprovides the desired therapeutic effects by amplification of synaptictransmissions through its enhancement of retinal ACh levels andmuscarinic receptor functionality, thereby improving the quality ofinformation destined for the occipital lobe of the brain. Specifically,the present inventor's unexpected success in reversing CNS-based visualloss related to, among other things, amblyopia, optic neuritis andParkinson's disease has been disclosed. Furthermore, a muscarinic basisto the present effect is established here, through the induction ofcycloplegic paralysis (using cyclopentolate). If induced on the morningimmediately following treatment with low-dose echothiophate, one canobserve no loss of subject vision gains, but if induced at day 4-5,there is significant, premature reversal of the effect.

The U.S. Pat. Nos. 6,273,092, 6,540,990 and 6,605,640, the contents ofwhich are incorporated herein by reference, disclose details regardingtreatment of various eye disorders using AChE inhibitor drugs.

Briefly, Acetylcholine esterase inhibitors are known to one skilled inthe art. There are at least two AChE inhibitor drugs currently approvedfor clinical use on the eye in the United States. They are(2-mercaptoethyl) trimethylammonium iodide O,O-diethyl phosphorothioatesold as PHOSPOHLINE IODIDE® (Wyeth-Ayerst, Philadelphia, Pa.), andphysostigmine (also known as eserine) sold as ANTILRIM® (ForestPharmaceuticals, St. Louis, Mo.). PHOSPHOLINE IODIDE is dispensed aseyedrops at a desired potency. PHOSPHOLINE IODIDE of variousconcentrations, such as for example 0.25%, 0.125%, 0.06% and 0.03% and apharmaceutically acceptable sterile diluent to dilute the concentratedform of this drug are commercially available. PHOSPHOLINE IODIDE iscurrently used for glaucoma and accommodative esotropia. As such,PHOSPHOLINE IODIDE is not a preferred drug even to treat glaucoma andaccommodative esotropia because of many adverse side effects caused bythis drug when it is used in the current regimen of multiple times a dayat high concentrations. Some of the side effects known to be caused bythe currently recommended doses of this drug (for glaucoma at 0.12 and0.25 BID) are iris cysts, cataract formation especially anteriorsubcapsular, posterior synechiae and elevated intraocular pressure.

In the present method, the cholinesterase inhibitor, such as phospholineiodide, administered in concentrations many fold more dilute thancurrently available pharmacological preparations, applied to the eyebefore sleep will achieve alleviation of the deteriorated ordeteriorating vision with none of the unacceptable side effects of theusual pharmacological preparations and without the loss of peripheralvision. The effect of one administration of the inhibitor can last formany days. The present invention shows that the effective concentrationof AChE inhibitor in the composition to treat diseases associated withthe posterior region of the eye can be very low (for example, as low asat least 0.001% to about 0.0075% of PHOSPHOLINE IODIDE) to be effective.The invention discloses that such a concentration is extremely usefulmedically. Specifically, this lower dose range is especially useful inproviding eye drugs that will contain a concentration of AChE inhibitorthat is low enough to be both safe and effective. For example, oneapplication of a drop of a suitable composition containing 0.03%PHOSPHOLIE IODIDE is sufficient for few days.

The composition administered to the eye should have a pharmaceuticallyacceptable carrier and a selected AChE inhibitor suspended or dissolvedin the carrier. The concentration of AChE inhibitor in the compositionadministered to the eye and the method of administration of thecomposition in accordance with this invention depends on the type ofAChE inhibitor containing composition used for therapy. For example,preferred concentrations of PHOSPHOLINE IODIDE in the PHOSPHOLINE IODIDEcontaining composition are from about 0.25% to about 0.001%. Morepreferred PHOSPHOLINE IODIDE concentrations are from about 0.15% toabout 0.005%. Most preferred PHOSPHOLINE IODIDE concentrations are about0.12%, 0.03% and 0.0075%. Still more preferred concentrations are about0.01%, 0.015% and 0.02%. It is preferred to apply PHOSOSPLIE IODIDEtopically to the eyes in the form of eye drops. Although it is preferredthat these solutions with various concentrations of PHOSPHOLINE IODIDEare stored in a refrigerator, they an be stored at room temperature forabout two months or even beyond two months without losing their efficacyto restore near vision in presbyopic patients.

A solution containing chlorobutanol (0.55%), mannitol (1.2%) boric acid(0.6%) and exsiccated sodium phosphate (0.026%) can be used as a carriersolution and/or as a diluent for PHOSPHOLINE IODIDE. While this solutionis presently sold as a diluent in the kit containing PHOSPHOLINE IODIDE,other pharmaceutically acceptable carriers or excipients that are knownto enhance membrane permeability and cellular uptake of the drug can beused as diluents with or without modification for application to theeye. Such carriers are known to one skilled in the art.

In a preferred embodiment of the invention, the AChE inhibitor isadministered at bedtime. A single topical application of a given AChEinhibitor at bedtime can enhance visual acuity in the phakic emmetropicpatients as well as in pseudophakic patients for a few days. Forexample, application of one to two drops of PHOSPHOLINE IODIDE of aselected concentration at bedtime can alleviate the diminished vision ofthe patients for at least five days. Preferably, the following steps arefollowed every time AChE inhibitor is applied to the patient. The firststep is to read for about 30 minutes. The second step is to administeran AChE inhibitor of a selected concentration. The third step is tosleep. Without wishing to be bound by any theory or explanation, it isbelieved that the reading for about 30 minutes preconditions eye musclesand visual pathway to respond better to the AChE inhibitor treatments.It takes about 6 to 8 hours of sleep to notice the restoration. If oneis awaken in the middle of sleep, the individual may notice partialeffect but after 6 to 8 hours of sleep the effect will be maximized. Bythe term “bedtime” it is meant that the time when the patient goes tosleep for about 6 to 8 hours, regardless of whether it is during the dayor night time. The composition is administered at bedtime, i.e., a dropof the AChE inhibitor is administered just before the patient goes tosleep for about 6 to 8 hours.

In another preferred embodiment of the invention, the AChE inhibitor isadministered prior to sleep, i.e., a drop of the AChE inhibitor isadministered immediately before the patient closes his/her eyes for atleast four hours of continuous sleep. It is important that the patientdoes not awaken or open their eyes after taking the drop, as suchactivity will cause the drops to be cleared from the surface of the eyevia the tear ducts.

Accordingly, by practicing the present invention, one can achieve adefinite, measurable gain in visual acuity in patients with retinalvascular or choroidal vascular disease or other diseases or conditionsof the eye when the one is administered with the acetylcholinesteraseinhibitor, in the dilution and the manner outlined above. Increase invisual acuity can be measured by techniques well known to those skilledin the art. Although the mechanism of action is unknown, it is believedthat a suitable dose of AChE inhibitor administered at “bedtime” or“prior to sleep,” as defined herein, may allow the eye to accumulatesufficient stockpiles of acetylcholine by inhibiting acetylcholineesterase activity in the eye and strengthen the eye muscles leading tothe normal perfusion of the blood to the posterior region of the eyeballparticularly choroid blood vessels. Retinal and choroidal function andhealth are dependant on normal perfusion of these tissues.

Choroidal circulation and retinal perfusion are visibly increased,within the effects of low-dose echothiophate. This is supported bybefore and after fluorescent angiograms performed across trial subjects.Additionally, increased ciliary body activity increases blood flow toand from the choroid.

Although ophthalmic compositions containing acetylcholinesteraseinhibitors are known in the art (see, Cohen, 1966, American Journal ofOphthalmology, 62:303-312 and Physician's Desk Reference for Ophthalnicmedicines, 2001 (29^(th) edition), pp 321-323), it has been found thatwithin their traditional dosage regimens, these compositions do notexhibit the therapeutic effects desired herein. Further, these existingcompositions typically have to be applied two to three times a day. Ithas been found that such repeated administration is not optimal inpractice, because, inter alia, for optimal treatment the patient has tohave the medicament always available and the patient is disturbedseveral times a day. Such multiple administration of a drug, inparticular of an ophthalmic composition, leads generally to the problemof overdosing and underdosing.

Surprisingly, it has now been found that an ophthalmicacetylcholinesterase inhibitor such as Phospholine Iodide (ecothiophate)can be formulated for weekly or bi-weekly administration at low-dose,which administration provides therapeutic efficacy in the eye over about7 days and that such compositions are surprisingly well tolerated.Moreover the above-mentioned bi-weekly or weekly ophthalmic compositionsproduce a highly reliable and more beneficial clinical result in apatient treated therewith.

Therefore, in one aspect the present invention provides an ophthalmiccomposition suitable for weekly administration to the eye before sleep.The composition has an AChE inhibitor from about 0.001-0.25%. Preferredinhibitor is (2-mercaptoethyl) trimethylammonium iodide O,O-diethylphosphorothioate. Preferred concentrations of the inhibitor is 0.010%,0.015% and 0.020%. In one aspect of the invention, the concentration ofthe inhibitor does not exceed 0.025% and is used only for weeklyadministration. The low-dose echothiophate as referred to herein is thatcomposition which has the ecothiophate at a concentration less than0.03% and/or is applied no more than twice a week at the rate of onedrop per each application. Thus, the low-dose echothiophate can beacheived by adjusting the solution strength (e.g., 0.001-0.025%) and/ormodifying the frequency of administration (bi-weekly or once a week). Itis preferred to adjust the solution strength rather than modifying thefrequency of administration. Such The application of a long-actingcholinesterase inhibitor (AChE), such as ECHO, permanently blocks thebinding sites of existing cholinesterase enzymes, halting theirbreakdown of acetylcholine. Levels of acetylcholine remain artificiallyelevated until the body naturally replaces these inactivatedcholinesterase enzymes (3-5 days) (Pappano A. J., 1998Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs, In Basic andClinical Pharmacology, 7th Edition, (Katzung, B. G., ed) Appleton &Lange, pp. 93-94). One indicative effect of this solution is astrengthening of ciliary-based accommodative potential. An increase inaccommodative amplitude can be measured for 4-6 days.

A drop of the compositions of the present invention amounts to about10-100 μl (microliters), preferably about 20-70 μl, and especially about25-50 μl and more preferably about 30 μl. It is preferred that drops areapplied inside the patient's lower eyelid. While administering the drop,patient may PINCH the bridge of their nose to block drainage into thetear ducts, then to continue compressing the tear ducts for two minutespost-application. Instead of drops, the composition may also be designedas controlled release forms, a dermal patch for application on thesurface of the eyelids or in the form of a collagen lens for laying overthe eye to be treated at bedtime or prior to sleep.

Mammals in the present invention include not only humans but also otheranimals selected from a group consisting of mice, rats, rabbits, pigs,cows, goats, dogs, cats and monkeys.

All publication references, patents and patent applications mentioned inthis specification are indicative of the level of those skilled in theart to which this invention pertains. The contents of all thepublications, patents and patent applications are herein incorporated byreference to the same extent as if each individual publication, patentor patent application was specifically and individually indicated to beincorporated by reference.

EXAMPLES

The examples below are carried out using standard drug administrationtechniques, that are well known and routine to those of skill in theart, except where otherwise described in detail. The examples areillustrative, but does not limit the invention. These examplesillustrate among other things (1) the alleviation of diminished visualacuity in humans suffering from diseases or disorders of the anteriorand/or posterior segment(s) of the eye and (2) potentiation of baselinenormal vision by topical administration of an AChE inhibitor to the eye.

Thirty three patients were studied with ages 11-76 Etiology varied fromamblyopia to Stargardt diseases. All of the patients studied showedvisual acity improvments after low-dose AchE inhibitor, PHOSPHOLINEIODIDE (also referred to herein as ECHO), treatment. Medications wereapplied prior to sleep. The dosage regimen was such that patients willbegin therapy using the opthalinc composition containing the AchEinhibitor at a concentration of 0.015% applied to one eye on Sundayevening and the alternate eye every Wednesday evening. Thereby, each eyereceived one drop per week. Most patients realized visual acuityimprovements with a solution of 0.015% strength. During the course oftreatment, it was found that in select cases, this 0.015% dosage was notwell tolerated by older patients and pseudophakic patients. A lowerdosage of 0.010% was then introduced.

Conversely it was found that young eyes (age 11-15) appeared to showreduced absorption of the 0.015% solution, relative to the olderpatients. Those patients, who displayed this reduced absorption (asevidenced by a lack of pupillary constriction) the dosages wereincreased to 0.020%. Drops were applied inside the patient's lowereyelid. The patients were advised to apply drops just before the patientcloses his/her eyes and have at least for three to four hours ofcontinuous sleep. Patients were advised to not awaken or open their eyesafter taking the drop, as such activity will cause the drops to becleared from the surface of the eye via the tear ducts.] Whileadministering the drop, patients were advised to pinch the bridge oftheir nose to block drainage into the tear ducts, then to continuecompressing the tear ducts for two minutes post-application.

All patients were given pre treatment comprehensive examinations andpatients monitored their visions during the treatment period. Theimprovement in visual acuity was immediate and generally noticed on thefirst day or week of treatment. The patient treatment results arepresented in table below. TABLE ONE Examples of visual acuityimprovements within low-dose echothiophate human subjects. Near VisionColor Vision Distant Vision (Jaeger) (Ishihara) Subject Pre- Post- Pre-Post- Pre- Post- Initials Sex Condition Dosage ECHO ECHO ECHO ECHO ECHOECHO BB2 F Amblyopia 0.010 20/200 20/200 18   16⁻¹⁺¹ 0 5 NM M Amblyopia0.015 20/70 20/50⁺²  1 1 10 10 WD2 F Amblyopia 0.010 20/50²⁺³ 20/30⁻²  72 10 10 DK M Brain Tumor 0.015 20/70 20/70⁺²  3  1⁺ 8 10 BB F CerebralStroke 0.015 20/50 20/40⁻¹  7⁻  2⁻¹ 1 1 BH M Central Serous 0.015 20/30020/70⁻ 16  1⁻² 2 8 Chorioretinopathy AV M Diab. Retinopathy 0.015 20/7020/30⁻¹  7⁺  3⁺ N/A N/A BR F Diab. Retinopathy 0.010 20/1600 20/1600 18 18⁻¹ 0 0 EM M Diab. Retinopathy 0.010 20/25⁻ 20/20⁻   1⁻¹ 1 10 10 TY MDiab. Retinopathy 0.010 20/50⁻ 20/50⁺ 16 16  N/A N/A CO F Macular Hole0.015 20/100⁻ 20/70⁻¹ 16  3⁻ N/A N/A TO M Macular Hole 0.015 20/160020/200  18⁺ 10  N/A N/A KC F Migraine/Amblyopia 0.015 20/8000 20/1600100  54  2 8 JJ F Optic Neuritis 0.015 20/100⁻ 20/25⁺  5  1⁺ 10 10 MM MOptic Neuritis 0.015 20/40 20/25⁺  3⁻ 1 0 0 HN M Parkinson's 0.015 20/4020/20⁺²  3 1 10 10 BC F Photocoagulation 0.010 20/70 + 2 20/70 + 3 5 − 13 − 2 7 8 PB M Photocoagulation 0.010 20/40 20/25  2+ 1 +− 1 10 10 RD2 MPhotocoagulation 0.015 20/1600 20/400 20 18  0 0 VC F Photocoagulation0.010 20/2667 20/400 20/800 16  0 1 CR F Preretinal Fibrosis 0.01520/30⁻¹ 20/25⁺¹   1⁻¹  1⁻ 10 10 TL M Retinal Detachment 0.010 20/25⁻20/20⁻¹  5 5 10 10 VD F Retinal Hole 0.015 20/100 20/100⁺⁺ 16  3⁺² 10 10SB F Retinal Vein 0.010 20/1600 20/1000 16 16⁺ 2 8 Occlusion KH2 FRetinitis Pigmentosa 0.015 20/400 20/70⁻¹  7⁻ 2 0 N/A ED M RetinitisPigmentosa 0.015 20/8000 20/70 16 7 0 8 RH2 M Retinitis Pigmentosa 0.01520/4000 20/2000 16 10  0 0 VD2 M Retinitis Pigmentosa 0.015 20/30⁻³20/25⁺⁴⁻²  7  1⁺ 5 8.5 SL M Solar Retinopathy 0.010 20/30⁻¹ 20/25 N/AN/A N/A N/A AF F Stargardts 0.015 20/1600 20/200 5″/J2 1 0 10 AG MStargardts 0.015 20/300 20/100⁻¹ 10  1⁻ 7 10 GP M Stargardts 0.01520/300 20/400 3″/J2 6″/J2 N/A N/A KH F Stargardts 0.015 20/200⁺¹20/100⁻¹⁺³  5⁻ 1 10 10Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it will be obvious that certain changes and modificationsmay be practiced within the scope of the appended claims.

1. A method of preventing, reducing and reversing ocular neuronal damagerelated to conditions affecting the visual system of a mammal,comprising: administration to one or both eyes of a mammal affected byor vulnerable to ischemic ocular neuronal damage, an amount of aacetylcholine esterase inhibitor containing composition sufficient toprovide a therapeutic benefit.
 2. The method of claim 1, wherein thecomposition is administered immediately prior to sleep.
 3. The method ofclaim 2, wherein said inhibitor is (2-mercaptoethyl)methylammoniumiodide O,O-diethyl phosphorothioate.
 4. The method of claim 3, whereinsaid (2-mercaptoethyl)trimethylammonium iodide O,O-diethylphosphorothioate is present at a concentration of 0.001% to 0.25%. 5.The method of claim 2, wherein the acetylcholine esterase inhibitor iscontained in a pharmaceutically acceptable buffer medium.
 6. The methodof claim 1, wherein the ocular neuronal damage relates to at least onecondition or disorder selected from the group consisting of: maculardegeneration, retinitis pigmentosa, optic neuritis, optic neuropathy,generalized optic nerve ischemia, neuroretinitis, Lebers congenitalamaurosis, Stargardt disease, Parkinson's disease, diabetic retinopathy,idiopathic senile vision loss, uveitis, edema, ocular surgery, athromboembolic event in the retinal vasculature, a visual scotoma, aretinal migraine, ophthalmoplegic migraine or scintillating scotoma,central retinal artery/vein occlusion, branch retinal artery/veinocclusion, anterior ischemic optic neuropathy, giant cell arteritis,retinal hemorrhage, cystoid macular edema, macular cystic degeneration,preretinal fibrosis, ischemic maculopathy, macular holes and cysts,macular epithelial fibrosis, peripapillary staphyloma and peripapillaryatrophy, acute macular neuroretinopathy and/or Plaquenil-relatedtoxicity.
 7. A method of improving visual acuity in a patient in needthereof and suffering from at least one condition or disorder selectedfrom the group consisting of: amblyopia, brain tumor, cerebral stroke,central serous chorioretinopathy, diabetic retinopathy, macular hole,retinal migraine, scintillating scotoma, optic neuritis, Parkinson'sdisease, photocoagulation, preretinal fibrosis, retinal detachment,retinal hole, retinal vein occlusion, retinitis pigmentosa, solarretinopathy and Stargardt disease.
 8. The method of claim 7, wherein thecomposition is administered prior to sleep.
 9. The method of claim 8,wherein said inhibitor is (2-mercaptoethyl)trimethylammonium iodideO,O-diethyl phosphorothioate.
 10. The method of claim 9, wherein said(2-mercaptoethyl)trimethylammonium iodide O,O-diethyl phosphorothioateis present at a concentration of 0.001% to 0.25%.
 11. The method ofclaim 10, wherein the concentration of(2-mercaptoethyl)trimethylammonium iodide O,O-diethyl phosphorothioateis 0.001%.
 12. The method of claim 10, wherein the concentration of(2-mercaptoethyl)trimethylammonium iodide O,O-diethyl phosphorothioateis 0.0075%.
 13. The method of claim 10, wherein the concentration of(2-mercaptoethyl)trimethylammonium iodide O,O-diethyl phosphorothioateis 0.010%.
 14. The method of claim 10, wherein the concentration of(2-mercaptoethyl)trimethylammonium iodide O,O-diethyl phosphorothioateis 0.015%.
 15. The method of claim 10, wherein the concentration of(2-mercaptoethyl)trimethylammonium iodide O,O-diethyl phosphorothioateis 0.02%.
 16. The method of claim 10, wherein the concentration of(2-mercaptoethyl)trimethylammonium iodide O,O-diethyl phosphorothioateis 0.03%.
 17. An ophthalmic composition comprising anacetylcholinesterase inhibitor in an ophthalmic buffer solution, whereinthe acetylcholinesterase inhibitor is present at a concentration of lessthan 0.03%.
 18. The composition of claim 17, wherein the composition isadministered once weekly, prior to sleep.
 19. The composition of claim17, wherein said inhibitor is (2-mercaptoethyl)trimethylammonium iodideO,O-diethyl phosphorothioate.
 20. The composition of claim 17, whereinsaid (2-mercaptoethyl)trimethylammonium iodide O,O-diethylphosphorothioate is present in said composition at a concentration ofabout 0.015%.